Cytokine-activated signaling pathways are the key determinants of the production, differentiation and state of functional activation of hematopoietic cells involved in host defense and inflammatory reactions. These pathways include both positive signaling intermediates (including kinases and latent transcription factors) and negative feedback pathways that limit the responses of cells to those appropriate to the situation. Our discovery of the Suppressor of Cytokine Signaling (SOCS) family of proteins and determination of their physiological importance using specific gene-deleted mice has identified these proteins as key inhibitors of excessive inflammatory responses in vivo. In particular, SOCS3 was shown to be the critical SOCS protein inhibiting the formation and function of granulocytes and macrophages in response to cytokines like G-CSF and IL-6 and to have a previously unsuspected role in maintaining the appropriate specificity in cellular responses to these cytokines. We have generated several important reagents including genetically modified mice where the roles of SOCS3 in specific cell types and the roles of specific domains in SOCS3 or the corresponding receptors can be determined at the whole animal, cellular and molecular levels. The major questions to be answered are: How do the different domains of SOCS3 interact with different intracellular components to mediate signal suppression? How does SOCS3 determine the specificity of the signaling pathways from these cytokines? Which hematopoietic and non-hematopoietic cells are affected by the actions of SOCS3 and what are their relative contributions to the inflammatory response? Do other SOCS proteins, at least to some extent, have similar actions to SOCS3 on hematopoietic cells? Answering these questions will allow us to define more clearly those disease conditions (inflammation, autoimmunity, infections, bone marrow transplantation for cancer chemotherapy) that would benefit from the use of SOCS3 agonists or antagonists as well as defining the best molecular targets to use for their screening.